title: Entering the lysosome through a transient gate by chaperone-mediated autophagy.
abstract: A subset of cytosolic proteins can be selectively degraded in lysosomes through chaperone-mediated autophagy. The lysosomal-membrane protein type 2A (LAMP-2A) acts as the receptor for the substrates of chaperone-mediated autophagy (CMA), which should undergo unfolding before crossing the lysosomal membrane and reaching the lumen for degradation. Translocation of substrates is assisted by chaperones on both sides of the membrane, but the actual steps involved in this process and the characteristics of the translocation complex were, for the most part, unknown. We have now found that rather than a stable translocon at the lysosomal membrane, CMA substrates bind to monomers of LAMP-2A driving the organization of this protein into a high molecular weight multimeric complex that mediates translocation. Assembly and disassembly of LAMP-2A into and from this complex is dynamic and it is regulated by hsc70 and hsp90, the two lysosomal chaperones related to CMA. This work thus unveils a unique mechanism of protein translocation across the lysosomal membrane, which involves only transient discontinuity of the membrane. The possible advantages of this transitory lysosomal translocon are discussed in light of the unique properties of the lysosomal compartment.
authors.affiliation: Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, New York 10461, USA.
authors.forename: Urmi
authors.initials: U
authors.lastname: Bandyopadhyay
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
mesh_terms: D000818:Animals; D001343:Autophagy; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones